We propose to develop a new class of biomaterials that will eliminate chronic inflammation, improve tissue regeneration and enhance wound healing at a biomedical device implant site by specifically controlling monocyte/macrophages (MO) differentiation and polarization. Uncontrolled or chronic inflammation has been strongly implicated in the foreign-body response and the encapsulation of biomedical devices and implants and impaired wound healing. Further, the lack of success in implementing stem cell regenerative medicine and tissue engineering can be linked to complications caused by chronic inflammation. Biomaterials capable of modulating MO behavior would thus have wide therapeutic potential, such as regulating tumor cells, mediating angiogenesis, and inducing the release of specific cytokines and growth factors to subsequently direct host inflammatory response towards healing. Monocytes are recruited to and accumulate at medical implant sites where they differentiate into MO or dendritic cells (DCs) and can be subsequently activated by local stimuli. Heterogeneity of activated MO can be broadly categorized as classically-activated "M1" cells that typically perform pro-inflammatory functions, or alternatively-activated "M2" cells that are generally associated with anti-inflammatory properties. M1 cells can be generated in vitro by activation of monocyte-derived cells using interferon-3 (IFN-3) and lipopoly- saccharide (LPS), while M2 cells can be generated by activation with interleukin-4 (IL-4). It has been suggested that chronic inflammation can arise from an imbalance between these two cell types. Thus, we propose to design model biomaterials that will resolve chronic inflammation by controlling MO differentiation and polarization. To achieve this goal, (1) cell-specific markers for M1 and M2 cells must be identified, which would allow for sub-population quantification and (2) biotherapeutic molecules must be identified that either attract or modulate desired sub-populations of activated MO. M1 or M2 cell-specific markers could also be used to target the delivery of these biotherapeutic agents to their respective subpopulations of activated MO. PUBLIC HEALTH RELEVANCE: This application seeks to advance our understanding of the molecular and cellular mechanisms of inflammation resolution and to use this knowledge to develop biomaterials that can spatial and temporal control the inflammatory tissue microenvironment.